Control of the Survival Pathways in TH17 Cells

Project Summary Despite their function in host defense, TH17 cells play a pathogenic role in many inflammatory and autoimmune diseases. Although several biologics and inhibitors are promising, there are currently only limited treatments for TH17-mediated diseases. Activating the death pathways in TH17 cells, which may control the diseases at the root, remains elusive and represents a critical gap in our knowledge. TH17 cells, due to the expression of high levels of the anti-apoptotic protein FLIP, are resistant to activation-induced cell death (AICD). In addition, TH17 cells are refractory to the broadly used steroid treatments in many inflammatory disorders. Therefore, we explored non-steroid pathways that control TH17 cell function and survival. TH17-promoting cytokines, including IL-6, IL-23, and IL-21, activate STAT3 and play essential roles in the differentiation, function, and maintenance of TH17 cells. Recently, we found that the endoplasmic reticulum (ER) stress-unfolded protein response (UPR) factor IRE1 (termed IRE1, hereafter), activated by the signals of cytokines IL-23 and IL-6 and those of TCR engagement and costimulation, contributes to the expansion of ER capacity and autophagy, leading to the enhancement of secretory function and the restoration of cellular homeostasis in TH17 cells. The signals of these cytokines and TCR/costimulation converge at STAT3 and IRE1. We thus hypothesize that targeting both IRE1 and STAT3 pathways may result in TH17 cell death and therefore, diminish the pathogenic function of these cells. Our preliminary study, demonstrating that simultaneous inhibition of IRE1 and STAT3 leads to massive TH17 cell death, strongly supports this. This proposal will initiate to explore the mechanisms of the induction of TH17 cell apoptosis and study the potential applications of this approach by using preclinical animal models.